The overall objective of the proposed research project is to discover bioactive marine natural products that lead to novel chemotherapeutics for the treatment of pancreatic cancer. Although eleventh in occurrence, pancreatic cancer is the fourth cause of cancer death in the US, with over 34,000 deaths predicted for 2009. Aggressive new combination chemotherapeutic regimes coupled with surgery have resulted in an overall increase in mean survival rate, but even so, fewer than 5% of patients diagnosed with pancreatic cancer will survive five years post diagnosis. Clearly, novel therapeutics are required to treat pancreatic cancer. During the first performance period of the project we made advancements towards the development of new treatments for pancreatic cancer, including findings such as: the discovery of leiodermatolide, a potent antimitotic agent with selective activity for tumor cells that effects microtubule dynamics but not though direct binding to tubulin;neopeltolide, a polyketide that inhibits mitochondrial ATP synthesis through inhibition of the cytochrome bc1 complex;and the finding that manzamine A can restore anchorage dependent growth in pancreatic cancer cells, block tumor cell migration and re-sensitize the ASPC-1 pancreatic adenocarcinoma cancer cell line to TRAIL induced apoptosis. In this renewal application we seek to continue to use a forward chemical genetics approach to build upon these successes.
The Specific Aims of the proposed research are: 1. To assay materials from the HBOI marine specimen frozen repository for their ability to 1.1. modify levels of key proteins that have been identified as aberrantly activated in pancreatic cancers and which lead to cancer cell survival, resistance to apoptosis and resistance to currently available chemotherapeutic agents;and block the proliferation of a panel of pancreatic cancer cell lines 2. To utilize state-of-the-art MS and NMR techniques for rapid and accurate dereplication and structure elucidation of candidate compounds. 3. To elucidate the mode of action of materials discovered during the project and to take those compounds which give the best biological profiles forward into experimental models of pancreatic cancer. HBOI maintains a repository of over 20,000 frozen marine specimens which represent a unique collection of natural products for drug discovery. We will use the cytoblot assay to identify small molecules that target pathways that are aberrantly activated in pancreatic cancers and which lead to poor survival rates in patients. Our initial targets will be: the serine/threonine glycogen synthase kinase-32 (GSK-32) which has been shown to activate nuclear factor-kB (NF-kB) transcription in pancreatic cancer cells leading to cell survival and proliferation;and the MAP kinase members P-MEK and P-ERK which are constitutively activated leading to cell survival, invasion and resistance to apoptosis. We will also continue to screen materials against a panel of pancreatic cancer cell lines. Animal models will be conducted at MD Anderson, Orlando.
This project will continue our past successes and lead to new, urgently needed chemotherapeutics for the treatment of pancreatic cancer. The compounds discovered under this project may be used as drugs themselves, modified to provide drugs with improved pharmacological properties or be used as biochemical tools to further understand pancreatic cancer.
|Guzmán, Esther A; Harmody, Dedra; Pitts, Tara P et al. (2017) Inhibition of IL-8 secretion on BxPC-3 and MIA PaCa-2 cells and induction of cytotoxicity in pancreatic cancer cells with marine natural products. Anticancer Drugs 28:153-160|
|Guzmán, Esther A; Xu, Qunli; Pitts, Tara P et al. (2016) Leiodermatolide, a novel marine natural product, has potent cytotoxic and antimitotic activity against cancer cells, appears to affect microtubule dynamics, and exhibits antitumor activity. Int J Cancer 139:2116-26|
|Guzmán, Esther A; Maers, Kelly; Roberts, Jill et al. (2015) The marine natural product microsclerodermin A is a novel inhibitor of the nuclear factor kappa B and induces apoptosis in pancreatic cancer cells. Invest New Drugs 33:86-94|
|Guzmán, Esther; Maher, Michael; Temkin, Alexis et al. (2013) Spongiatriol inhibits nuclear factor kappa B activation and induces apoptosis in pancreatic cancer cells. Mar Drugs 11:1140-51|
|Russell, Floyd; Harmody, Dedra; McCarthy, Peter J et al. (2013) Indolo[3,2-a]carbazoles from a deep-water sponge of the genus Asteropus. J Nat Prod 76:1989-92|
|Kallifatidis, Georgios; Hoepfner, Dominic; Jaeg, Tiphaine et al. (2013) The marine natural product manzamine A targets vacuolar ATPases and inhibits autophagy in pancreatic cancer cells. Mar Drugs 11:3500-16|
|Guzmán, Esther A; Johnson, Jacob D; Linley, Patricia A et al. (2011) A novel activity from an old compound: Manzamine A reduces the metastatic potential of AsPC-1 pancreatic cancer cells and sensitizes them to TRAIL-induced apoptosis. Invest New Drugs 29:777-85|
|Winder, Priscilla L; Baker, Heather L; Linley, Patricia et al. (2011) Neopetrosiquinones A and B, sesquiterpene benzoquinones isolated from the deep-water sponge Neopetrosia cf. proxima. Bioorg Med Chem 19:6599-603|
|Paterson, Ian; Naylor, Guy J; Gardner, Nicola M et al. (2011) Total synthesis and biological evaluation of a series of macrocyclic hybrids and analogues of the antimitotic natural products dictyostatin, discodermolide, and taxol. Chem Asian J 6:459-73|
|Paterson, Ian; Dalby, Stephen M; Roberts, Jill C et al. (2011) Leiodermatolide, a potent antimitotic macrolide from the marine sponge Leiodermatium sp. Angew Chem Int Ed Engl 50:3219-23|
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